Pertuzumab e Trastuzumab-DM1.

Filippo Montemuro, M.D.

Divisione di Oncologia Medica 1

Fondazione del Piemonte per l’Oncologia/Istituto per la Ricerca e la Cura del Cancro, Candiolo

HER2 targeting has changed the natural history of HER2-positive advanced breast cancer

Dawood et al, J Clin Oncol 28;92, 20091991-2007

Proposed Mechanisms of Action of Trastuzumab

Spector, J Clin Oncol 27;5838, 2009

From linear cascades to integrated networks

Evolutionary processes: Gene Duplication Subfunctionalization (i.e. HER2 no known ligands, HER3 no

tyrosine kinase activity)

Amit I, Wides R, Yarden Y, Molecular Systems Biology 2007

1 ligand 10 ligands

Targeting key pathways in HER signalling…and beyond

LapatinibNeratinibBIBW 2992CanertinibErlotinibGefitinib

Trastuzumab/DM1PertuzumabMM-111

PertuzumabCixitumumab

EverolimusTemsirolimus

ADAM 17 inhibitors

HDAC inhibitors

Endothelial Cell

VEGFR

PDGFR

PDGF

VEGF

BevacizumabSorafenibSunitinibPazopanib

HSP90Inhibitors

HER2:HER3 dimers may provide an escape mechanism from trastuzumab

++++

+++++++

Signaling activity

+ +++

Homodimers Heterodimers

HER1:HER1HER2:HER2

HER3:HER3HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3

HER2:HER4HER3:HER4

Tzahar, et al. Mol Cell Biol 1996Tzahar et al. Mol Cell Biol 1996;

Sergina et al. Nature 2007

Different mechanisms of action of trastuzumab and pertuzumab on heterodimers

Activity of pertuzumab in HER2-negative breast cancer

Gianni et al. J Clin Oncol, 28; 1131, 2010

Toxicity profile of pertuzumab

Gianni et al. J Clin Oncol, 28; 1131, 2010

8 patients experienced drops in LVEF ≥10% to <50%, including 1 CHF

Pertuzumab, demonstrates synergistic activity with trastuzumab

● Preferentially inhibits ligand-independent HER2 signaling

● Prevents shedding of HER2 ECD● Flags cells for destruction by the

immune system

● Inhibits formation of HER2 dimer pairs● Suppresses multiple HER signalling pathways,

leading to a more comprehensive blockade of HER2-driven signalling

● Flags cells for destruction by the immune system

HER2 receptor

TrastuzumabPertuzumab

Subdomain IV of HER2

Dimerization domain of HER2

Junttila et al. Cancer Cell 2009

Activity of trastuzumab and pertuzumab in HER2 positive xenografts

Scheuer et al, Cancer Res 2009

Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy

Pertuzumab + trastuzumab

(n=66)

Cohorts 1 and 21

HER2-positive MBC Progressed on trastuzumab +

chemotherapy (Cohorts 1 and 2, n=66)

HER2-positive MBC Progressed on trastuzumab +

chemotherapy (n=29)

Pertuzumab(n=29)

Pertuzumab + trastuzumab

(n=15)Cohort 32

Primary objectives● Safety and efficacy

Population● ≤3 prior lines cytotoxic therapy (including adjuvant treatment)

1. Baselga et al. JCO 2010; 2. Baselga et al. SABCS 2009

Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone

Cohorts 1 and 21,2

(P + H) (n=66)

Cohort 33 (P)

(n=27*)

Cohort 33 (P P + H)

(n=11†)

CR, % 7.6 0.0 0.0

PR, % 16.7 3.4 21.4

ORR, % 24.2 3.4 21.4

SD 6 months, % 25.8 6.9 21.4

CBR, % (CR + PR + SD 6 months)

50.0‡ 10.3 37.5

PD, % 50.0 82.8 57.1

1. Gelmon et al. ASCO 2008; 2. Baselga et al. JCO 2010;

3. Baselga et al. SABCS 2009CR, complete response; PR, partial response; SD, stable disease

*n=27, as at data cut-off 2/29 patients had not reached overall best response endpoint (8 cycles of assessment during this phase); †n=11, as at data cut-off 4/15 patients had not reached overall best response endpoint(8 cycles of assessment during this phase); ‡at data cut-off, 21 (31.8%) patients had not experienced PD

Toxicity, non cardiac

Baselga et al, J Clin Oncol, 28;1138, 2010

Cardiac toxicity

Baselga et al, J Clin Oncol, 28;1138, 2010

Further development of this combination

Accrual completedAccrual completed

HER2-positive MBC No prior chemotherapy for MBC

(except 1 prior hormonal regimen)(n=800*)

Trastuzumab + docetaxel +

placebo

Trastuzumab + docetaxel + pertuzumab

1:1

Cleopatra

HER2-positive MBC 2nd line, progressed on prior trastuzumab

(n=450)

Trastuzumab + capecitabine +

placebo

Trastuzumab + capecitabine +

pertuzumab

1:1

125 centers, 20 countries125 centers, 20 countries

Pherexa

The NEOSPHERE trial

Trastuzumab + Docetaxel

Trastuzumab + Docetaxel + Pertuzumab

Trastuzumab + Pertuzumab

Docetaxel + Pertuzumab

Surgery

FEC X 3 trastuzumab q3w until week 52

FEC X 3 trastuzumab q3w until week 52

Trastuzumab + Docetaxel

FEC X 3 trastuzumab q3w until week 52

HER2+LABC

400 patients

FEC X 3 trastuzumab q3w until week 52

End Points:-pCR-Biomarker analysis

Gianni et al. SABCS 2011

Gianni et al. SABCS 2011

Gianni et al. SABCS 2011

Gianni et al. SABCS 2011

Gianni et al. SABCS 2011

Gianni et al. SABCS 2011

PI3K inhibition

Multiple targeting with trastuzumab, pertuzumab and GDC-0941

Trastuzumab-DM1

T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells

Receptor-T-DM1 complex is internalized into HER2-positive cancer cell

Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

T-DM1 binds to the HER2 protein on cancer cells

• Trastuzumab-like activity by binding to HER2• Targeted intracellular delivery of a potent antimicrotubule

agent, DM1

Phase I study in patients with HER2-positive advanced breast cancer

Phase I study in patients with HER2-positive advanced breast cancer

Clinical Study DescriptionsStudy TDM4258g (n=112) Study TDM4374g (n=110)

Study design Multi-institutional, single-arm Phase II US studies

Patient population (all with locally confirmed HER2-positive MBC)

Received prior chemotherapy for MBC

Progressed after exposure to at least one HER2-directed therapy (trastuzumab)

Previously treated with an anthracycline, a taxane, capecitabine, lapatinib and trastuzumab

Received at least two HER2-directed regimens for MBC, and progressed on the last regimen received

Prior systemic therapy

Received a median of 3 prior chemotherapy agents for MBC (range 1–12)

All received prior trastuzumab; 67/112 (60%) patients had also received prior lapatinib

Received a median of 7 prior chemotherapy agents for MBC (range 1–15)

All received prior lapatinib and trastuzumab

Study treatmentT-DM1 (3.6 mg/kg) was given by IV infusion over 30–90 minutes every 3 weeks (q3w) until disease progression

Primary objectivesObjective response rate (ORR) per RECIST by independent review facility (IRF)

Antitumor Activity, All Treated Patients

TDM4374g* (n=110)

TDM4258g† (n=112)

ORR,% (95% CI)‡ 32.7 (24.1–42.1) 25.9 (18.4–34.4)

Clinical benefit rate, % (95% CI)§ 38.8 (38.8–57.9) 39.3 (30.3–48.3)

ORR=objective response rate.* Approximately 9 months minimum follow-up from last patient in (LPI)† Approximately 12 months minimum follow-up from LPI‡ Complete or partial response determined by 2 tumor assessments ≥ 28 days apart§ Includes patients who achieved an ORR, partial response, or stable disease of ≥ 6 months

• Both Phase II studies demonstrated clinically meaningful ORR for single-agent T-DM1.

Prior Chemotherapy and Anti-HER2 Therapy:TDM4258g

Summary of activity as a single agent: TDM4258g

Activity according to HER2 status

Adverse events

Patients treated with TDM1 retain sensitivity to further antiHER2-based therapy

Randomized, phase II, international, open-label study HER2-positive, measurable disease required Stratification factors

World region, prior adjuvant trastuzumab therapy, disease-free interval Primary endpoints: PFS by INV, safety Key Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control

Study Design

1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137)

T-DM13.6 mg/kg Q3W until PD

Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W

+ Docetaxel 75 or 100 mg/m2 Q3W

CrossoverT-DM1PD

Perez EA, et al. Abstr LBA3. ESMO 2010Perez EA, et al. Abstr LBA3. ESMO 2010

Objective Response by Investigator (ITT)Randomized Patients

T-DM1(n=67)

Trastuzumab + Docetaxel

(n=70)

Patients with an Objective Response,* n (%) 32 (47.8) 29 (41.4)

95% CI (35.4, 60.3) (30.2, 53.8)

Patients with Clinical Benefit,† n (%) 37 (55.2) 40 (57.1)

95% CI (43.1, 67.2) (44.8, 68.9)

Objective Responses, n (%)

Complete Response 3 (4.5) 1 (1.4)

Partial Response 29 (43.3) 28 (40.0)

Stable Disease‡ 22 (32.8) 29 (41.4)

Progressive Disease 8 (11.9) 4 (5.7)

Unable to Evaluate 4 (6.0) 4 (5.7)* Objective response = complete or partial response based on RECIST 1.0 determined on two consecutive tumor assessments at least 4 weeks apart† Clinical benefit = objective response or maintained stable disease for at least 6 months from start of study treatment‡ Stable disease includes 11 patients with unconfirmed partial response (5 in T-DM1 arm and 6 in the trastuzumab + docetaxel arm) Perez EA, et al. Abstr LBA3. ESMO 2010Perez EA, et al. Abstr LBA3. ESMO 2010

AE Summary Safety Evaluable Patients

T-DM1(n=67)

Trastuzumab+Docetaxel(n=68)

Any AE, n (%) 63 (94.0) 68 (100.0)

Grade ≥3 AE 25 (37.3) 51 (75.0)

Serious AE* 13 (19.4) 15 (22.1)

Three most common AEs (any grade) in T-DM1 arm Nausea Fatigue Pyrexia

32 (47.8)31 (46.3)24 (35.8)

27 (39.7)29 (46.2)14 (20.6)

Three most common AEs (any grade) in trastuzumab + docetaxel arm Alopecia Neutropenia Diarrhea

1 (1.5)5 (7.5)

7 (10.4)

45 (66.2)39 (57.4)31 (45.6)

* AEs that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies/birth defects

* AEs that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies/birth defects

Perez EA, et al. Abstr LBA3. ESMO 2010Perez EA, et al. Abstr LBA3. ESMO 2010

Phase Ib/II trial of T-DM1 + pertuzumab in patients with locally-advanced and MBC who were previously treated with trastuzumab

Phase Ib: 3+3 dose escalation• Cohort I: T-DM1 3.0 mg/kg; pertuzumab

(840 mg loading dose, 420 mg maintenance dose)• Cohort II: T-DM1 3.6 mg/kg; pertuzumab

(840 mg loading dose, 420 mg maintenance dose)Phase II

• Expansion at dose level established in Phase Ib

Dose escalation phase(completed)

Expansion phase(completed)

Phase Ib/II: HER2-positive MBC in all therapeutic lines

(n=67)

T-DM1 + pertuzumab

(n=9)

T-DM1 + pertuzumab

(n=58, including 22 first line)

Primary endpoints:• Safety• ORR by RECIST 1.0

Secondary endpoints:• PFS• DoR

Heavily pretreated population:• Median of 6 prior therapeutic agents in the metastatic setting

Miller et al. ASCO 2010

T-DM1 + pertuzumab shows promising efficacy in patients pretreated with trastuzumab + lapatinib

Cohort I, n (%) (n=3)

Cohort II, n (%) (n=25)

Total, n (%) (n=28)

PR 2 (66.7) 8 (32.0) 10 (35.7)

SD 1 (33.3) 12 (48.0) 13 (46.4)

PD 0 4 (16.0) 4 (14.3)

Missing 0 1 (4.0) 1 (3.6)

ORR was 35.7% (10/28 patients), per investigator assessment All responses were confirmed PRs 1/13 patients with SD had an unconfirmed response

Miller et al. ASCO 2010Miller et al. ASCO 2010

T-DM1 + pertuzumab has an encouraging safety and tolerability profile

Key AE, % Grade 3, % Grade 4, % Total (all grades), %*

Any Events 36.4 4.5 100

Fatigue 13.6 0 52.3

Nausea 4.5 0 5 .0

Thrombocytopenia 6.8 4.5 27.3

Diarrhea 2.3 0 25.0

Vomiting 4.5 0 22.7

AST increase 6.8 0 20.5

Dyspnea† 2.3 0 20.5

AST, aspartate aminotransferase Miller et al. ASCO 2010Miller et al. ASCO 2010

*One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This AE was considered to be unrelated to study treatment †Primarily attributed to pneumonia or the disease under study (lung metastases & pleural effusions)

*One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This AE was considered to be unrelated to study treatment †Primarily attributed to pneumonia or the disease under study (lung metastases & pleural effusions)

First-line T-DM1 + pertuzumab vs trastuzumab + docetaxel

Clinicaltrials.gov

Primary endpoints● PFS (independent assessment)● SafetySecondary endpoints● ORR (independent assessment)● OS● 1-year survival● PFS● ORR (investigator assessment)● CBR● TTF● DoR● Safety and tolerability

HER2-positive MBCNo prior chemotherapy

(n=1092)

Trastuzumab + taxane

T-DM1 + placebo

T-DM1 +pertuzumab

Global study starts summer 2010332 centers in 40 countries